Irinotecan is a semi-synthetic derivative of camptothecin. Camptothecin can specifically bind to topoisomerase I, which can induce reversible DNA single-strand breaks, and then unwind the DNA double-strand structure. Irinotecan and its active metabolite SN-38 can bind to topoisomerase I-DNA complex, thereby preventing re-connection of the single-stranded fracture. It has been proved that the cytotoxicity of irinotecan can be attributed to the interaction of replicase and topoisomerase I-DNA-irinotecan (or SN-38) triple complexes, which breaks DNA double-strand in DNA synthesis.
Irinotecan hydrochloride is widely used in the treatment of malignant tumor with the advantages of obvious pharmacological effects and clinical efficacy. However, it has the same problem with other camptothecin derivatives: the saturated lactone ring in irinotecan's structure is pH-dependent and can be transformed into its carboxylate form reversibly under physiological conditions, for which anti-tumor activity will be weakened. The existing commercial formulations of irinotecan hydrochloride are liquid injection and freeze-dried powder for injection. After intravenous administration in clinical, the free drug will lose activity because the lactone ring in its structure is prone to be hydrolyzed into the carboxylate form in the alkaline physiological environment, thereby reducing drug efficacy indirectly. And these formulations have serious side effects, which are mainly neutropenia and delayed diarrhea.
Liposome is widely studied as a drug carrier in recent years. The main features of liposome include protecting the encapsulated drug, increasing drug stability, changing the in vivo distribution behavior of drug, and carrying drug to the diseased region by passive or active targeting. As a good carrier of anticancer drugs, liposome can improve drug efficacy and reduce drug toxicity.
The international application WO2005/117878 disclosed a formulation of irinotecan liposome and preparation method thereof. This formulation comprises irinotecan or irinotecan hydrochloride, phospholipid selected from the group consisting of hydrogenated soybean phosphatidylcholine, phosphatidylethanolamine, lecithin and cardiolipin, and cholesterol. Similarly, the Chinese patent application CN1994279A also disclosed a formulation of irinotecan liposome and preparation method thereof, wherein phosphatidylcholine is used as a phospholipid to prepare a liposome in Example 5.
The formulations mentioned in the above patent literatures can achieve good effect. However, when those formulations are used in human, the stability, particle size and the like are still unsatisfactory.